Noise induced hearing loss has substantial impact on the productivity and quality of life for as many as 10 million people in the United States. There is increasing evidence from human and animal studies that mutations within genes expressed within the cochlea can render individuals more susceptible to hearing impairment caused by exposure to acoustic over- stimulation, trauma or ototoxic agents. We propose to search for NIHL susceptibility gene mutations by examining subjects who routinely receive high levels of noise exposure. A series of 2000 military personnel who are found to have permanent changes in hearing thresholds (PTS) during yearly audiological examination and 1000 control subjects will be screened for sequence variations that either directly or in combination with other factors are associated with NIHL susceptibility. PTS and control subjects will be compared for mutations in candidate genes, history of occupational noise exposure and other epidemiological factors (i.e., smoking, ethnic background, family history of hearing impairment). The gene mutations examined will include sequence variants associated with specific inherited forms of hearing impairment and sequence variations identified within candidate genes suspected to have important roles in maintenance of cochlear function. We suspect that an increased frequency of one or more inherited gene mutations will be found in PTS subjects relative to control subjects, perhaps as the result of being carriers for recessively inherited non-syndromic deafness traits (congenital), dominantly inherited hearing impairment genes with a later age of onset or one of several mitochondrial DNA mutations. We will identify PTS subjects with a family history of NIHL to identify families that will be suitable for future linkage and candidate gene localization studies. These studies represent an innovative approach toward identification of cochlear genes that have important roles in the protection and recovery from acoustic trauma caused by chronic acoustic over-stimulation.